The main objective of this study is to better understand cellular and molecular mechanisms of normal human brain development. I will particularly focus on the effect of sonic hedgehog (Shh) on progenitors of cortical interneurons. Cortical interneurons provide inhibitory input to pyramidal cells, and are necessary for normal function of the cerebral cortex. They are impaired in a number of psychiatric diseases, such as schizophrenia, autism and bipolar disorder. Evolutionary changes resulted in the more complex cerebral cortex of primates, including variety of cortical progenitors which divide in the large outer subventricular zone (oSVZ) of the human forebrain. Thus, in contrast to rodents where cortical interneurons mainly originate in the ganglionic eminence (GE) of the ventral telencephalon, in primates they can originate in the GE and in the cortical oSVZ. Late generated interneurons in the cortical oSVZ are destined for upper cortical layers which are necessary for higher brain functions that characterize humans. Thus, information derived from animal models, although very useful, cannot always be directly applied to humans. We propose two specific aims: 1. Distribution of sonic hedgehog (Shh) and its receptors in the human outer SVZ 2. The effect of Shh signaling on late cortical progenitors Cortical progenitors in the oSVZ of human mid-term (20 gestational weeks) brains obtained on autopsies will be studied by immunohistochemistry, in situ hybridization, and in vitro method including Cre-LoxP genetic labeling. Corresponding embryonic ages and regions in mice will be also studied. Cell culture will be used to investigate the role of sonic hedgehog signaling on genesis of human cortical interneurons from oSVZ progenitors. The experiments proposed here are expected to better characterize interneuron progenitor subtypes in the human cerebral cortex, and may be used as bases for future new therapeutic approaches, including cell replacement and stem cell therapies.

Public Health Relevance

Human cerebral cortex is the principal structure that makes us humans different from any other species. I will study how late generated cortical interneurons, which are potentially human- specific and involved in various neuro-developmental or psychiatric disorders, respond to environmental influences, such as sonic hedgehog (Shh).